Editorial: healing of refractory reflux oesophagitis – an ongoing unmet clinical need

Refractory GERD remains a challenging problem. The article by Kahrilas1 is timely and welcome but unfortunate that the analysis has provided no new clinical directions. In results, Kahrilas found ‘significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63% P = 0.039)’ and in discussion ‘patients with refractory oesophagitis had a significantly higher prevalence of frequent regurgitation at baseline than slow healers, and a trend towards a higher prevalence of frequent regurgitation vs. rapid healers'. We believe that including only patients who had regurgitation at baseline (37/46 vs. 47/75) was incorrect. Calculating the ‘prevalence’ taking all patients who had refractory oesophagitis vs. slow healing oesophagitis (37/49 vs. 47/78), the difference between the two groups is no longer significant (P = 0.086). Although 93% of patients had concomitant regurgitation at baseline, when the sample size is small, a small change in numbers can alter the results significantly. Therefore, comparisons between refractory oesophagitis and slow healing oesophagitis should be interpreted with caution. It is unclear which patient characteristics were ‘independent predictors’ in the regression model. The patient characteristics assessed did not cover all the baseline variables in the tables. It is not clear whether Kahrilas took any patients with regurgitation (86%), or those with only frequent regurgitation (59%). Conversely, it is not clear if ‘logistic regression analysis’ was also used to study ‘possible predictors’ for group B, although the authors claimed at ‘Week 4 possible predictors of refractory vs. slow healing RE were also assessed, but none was statistically significant’. If so, only four or fewer predictors should be put into the model, considering the small sample size of refractory patients (n = 49) since logistic regression models require a minimum of 10 events per variable. Hiatal hernia (HH) was significantly increased only in patients not healed at 2 weeks vs. rapid healers, but unexpectedly, HH was not increased in slow healers (69%) vs. rapid healers (64%) vs. refractory patients (51%); and was significantly lower in refractory patients vs. slow healers. The statement in discussion that ‘a higher proportion of patients with refractory reflux oesophagitis had HH at baseline than did rapid or slow healers’ is therefore incorrect. The authors suggested that this ‘may simply be due to the small sample sizes involved’; this is doubtful, because more than half the patients had HH and the sample size is not small, especially for rapid healers. The statement that ‘95% CIs for all mean QoLRAD scores overlapped, which may reflect the limited sample size after 8 weeks of therapy’ for refractory patients (n = 49) vs. slow healers (n = 78) and vs. rapid healers (n = 495) is incorrect. Overlapping 95% CIs do not indicate differences are nonsignificant, and are not necessarily related to sample size and here are not small for mean scores comparisons. Kahrilas1 confirmed the studies of the McMaster group (15–20 years ago), showing the complex relationship of acid suppression to oesophagitis healing2 and to speed of healing3; oesophagitis classification also impacts the evaluation of oesophagitis healing with PPIs4 and time pH <4 predicts the failure of oesophagitis to heal.5 Savarino6 found HH a negative predictor for normalising oesophageal acid exposure in refractory patients, which required an increased PPI dose, emphasising the importance of dose and duration of PPI anti-secretory effect. Dose and frequency of administration was a critical factor in the Cochrane review.7 We5 and others have emphasised unmet needs in the treatment of severe oesophagitis, which is, in part, due to the lack of an agreed definition of PPI refractory disease. With once-daily esomeprazole, 12.9% and 20.5% of LA grade C and D oesophagitis, respectively, are still unhealed after 8 weeks 8 (Table 1) and healing rate is time dependent.3, 7 Thus, 12 weeks might be considered a better ‘time point’ to determine oesophagitis ‘refractory’ to PPIs. We believe in a tailored approach.9 When the prescriber has the choice of equally potent but longer acting acid suppressants,10 rather than the current ‘one size fits all’ PPIs, refractory oesophagitis may become a disease of the past. Declaration of personal interests: Carmelo Scarpignato has served as a speaker, consultant and/or advisory board member for Alfa Wassermann, AstraZeneca, Boeheringer-Ingelheim, Giuliani Pharmaceuticals, Pfizer, Recordati, Sigma-Tau, Shire and Warner-Chilcott, and has in the past received funding from Giuliani Pharmaceuticals and Pfizer. Declaration of funding interests: None.

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